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Modulation of the poliovirus receptor expression in malignant lymphocytes by epigenetic alterations

Wei Wang1, Li Gao, Xinrong Wang

  • 1Department of Hematology, Chinese PLA General Hospital, Beijing, China.

Journal of Immunotherapy (Hagerstown, Md. : 1997)
|April 19, 2011
PubMed

Insights

Malignant lymphocytes resist natural killer (NK) cell therapy due to low poliovirus receptor (PVR) expression. Epigenetic modifications, specifically DNA methylation and histone deacetylase activity, were found to repress PVR, offering therapeutic targets.

Area of Science:

  • Immunology
  • Cancer Biology
  • Epigenetics

Background:

  • Malignant lymphocytes often exhibit low poliovirus receptor (PVR) expression, contributing to resistance against natural killer (NK) cell-mediated therapies.
  • PVR serves as a ligand for activating NK cell receptors, making its downregulation a critical factor in immune evasion by cancer cells.

Purpose of the Study:

  • To investigate the epigenetic mechanisms underlying the defective PVR expression in NK-insensitive malignant lymphocytes.
  • To explore the potential of epigenetic modulation to restore PVR expression and enhance NK cell-mediated cytotoxicity.

Main Methods:

  • Analysis of PVR mRNA and surface protein levels in NK-sensitive and NK-insensitive cell lines.
  • Assessment of PVR promoter-associated CpG island methylation status.
  • Treatment of cells with epigenetic modifiers: 5-azacytidine (5-AZA) and suberoylanilide hydroxamic acid (SAHA).
  • Evaluation of NK cell-mediated cytotoxicity against treated cells and assessment of PVR blockade effects.

Main Results:

  • NK-insensitive cell lines, including RAJI cells, displayed significantly lower PVR expression at both mRNA and surface levels.
  • Hypermethylation of PVR promoter-associated CpG islands was observed in NK-resistant RAJI cells.
  • Treatment with 5-AZA and SAHA partially reversed epigenetic abnormalities, restoring PVR expression.
  • Restored PVR expression on RAJI cells increased their susceptibility to NK cell killing, an effect diminished by PVR-blocking antibodies.
  • Patients with acute myeloid leukemia showed higher PVR expression compared to those with acute lymphoblastic leukemia.

Conclusions:

  • Epigenetic mechanisms, including DNA hypermethylation and histone deacetylase activity, play a crucial role in repressing PVR expression in malignant lymphocytes resistant to NK cell surveillance.
  • Targeting these epigenetic alterations presents a promising strategy to re-sensitize resistant cancer cells to NK cell-based immunotherapy.

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